It has been established that regenerating bone marrow induces an osteogenic response in distant skeletal sites and that this activity is mediated by factors released into the circulation by the healing tissue [(Bab I., et al. (1985) Calcif. Tissue Int. 37:551; Foldes, J., et al. (1989) J. Bone Min. Res. 4:643; Einhorn, T. A., et al. (1990) J. Bone Joint Surg. Am. 72:1374; Gazit D., et al. (1990) Endocrinology 126:2607; Mueller, M., et al. (1991) J. Bone Min. Res. 6:401]. One of these factors, a 14-amino acid osteogenic growth polypeptide (OGP) (SEQ ID NO: 1), identical with the C-terminus of histone H4, has been recently identified in the regenerating bone marrow [Bab, I., et al. (1992) EMBO J. 11:1867; EP-A-0 384 731] and in human serum [Greenberg, Z et al (1995) J. Clin. Endocrinol. Metab 80:2330].
Synthetic osteogenic growth polypeptide, identical in structure with the native molecule, has been shown to be a potent stimulator of proliferation of osteoblastic and fibroblastic cells in vitro. This synthetic polypeptide also stimulates osteoblastic cell alkaline phosphatase activity. When injected in vivo to rats, at very small doses, the synthetic osteogenic growth polypeptide increases bone formation and trabecular bone mass [Bab, I., et al (1992) EMBO J. 11:1867].
Since the OGP molecule is too large for effective oral administration, it is of therapeutic importance to identify peptides, shorter than the full length OGP, that retain the OGP activity and can be modified into a stable preparation, suitable for the oral treatment of several pathological conditions, particularly conditions involving loss of bone tissue. Indeed, it was shown that the C-terminal penta-peptide of OGP, Try-Gly-Phe-Gly-Gly[OGP(10-14)] (SEQ ID NO: 61), retains the full OGP-like proliferative activity in vitro and osteogenic effect in vivo [WO94/20529 corresponding to Israel Patent Application No. 104954]. Due to its small size, this penta-peptide provides a useful basis for the design of further OGP analogs with improved activity, stability and bioavailability.
In search for yet improved osteogenically active substances, the inventors have now found novel, synthetic pseudopeptide derivatives of OGP (SEQ ID NO: 1) and OGP(10-14) (SEQ ID NO: 61), which are the subject of the present application.
The present invention relates to pseudopeptidic osteogenic growth polypeptide (OGP) analogs having the general formula: 
wherein the substituents are as hereafter defined.
The invention also relates to cyclic peptidic or pseudopeptidic OGP analogs having the general formula: 
wherein the substituents are as hereafter defined.
The invention also relates to pharmaceutical compositions comprising as active ingredients the compounds of formulae (I) and/or (II).